title: Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) -targeted drugs in patients with non-small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC.
  
  
  METHODS
  Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety.
  
  
  RESULTS
  There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients.
  
  
  CONCLUSIONS
  Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.
authors.affiliation: David R. Spigel, Thomas J. Ervin, and Davey B. Daniel, Sarah Cannon Research Institute; David R. Spigel, Tennessee Oncology, Nashville; Davey B. Daniel, Chattanooga Oncology Hematology Associates, Chattanooga, TN; Thomas J. Ervin, Florida Cancer Specialists, Fort Myers; Michael S. Wertheim, Hematology/Oncology Associates, Port St Lucie, FL; Rodryg A. Ramlau, Poznan University of Medical Sciences, Poznan; Maciej J. Krzakowski, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Jerome H. Goldschmidt Jr, Blue Ridge Cancer Care, Christianburg, VA; George R. Blumenschein Jr, The University of Texas MD Anderson Cancer Center, Houston, TX; Gilles Robinet, University Hospital Morvan, Brest; Benoit Godbert, Centre Hospitalier Universitaire Nancy, Vandoeuvre-lès-Nancy; Fabrice Barlesi, Assistance Publique-Hôpitaux de Marseille, Aix Marseille University, Marseille, France; Ramaswamy Govindan, Washington University School of Medicine, St Louis, MO; Taral Patel, Mid Ohio Oncology/Hematology, Columbus, OH; Sergey V. Orlov, St Petersburg Pavlov State Medical University, St Petersburg, Russia; Wei Yu, Robert L. Yauch, Premal H. Patel, and See-Chun Phan, Genentech; Amy C. Peterson, Medivation, San Francisco, CA; and Jiping Zha, Crown Bioscience, Taicang City, China.
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ervin
authors.forename: Rodryg A
authors.initials: RA
authors.lastname: Ramlau
authors.forename: Davey B
authors.initials: DB
authors.lastname: Daniel
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Goldschmidt
authors.forename: George R
authors.initials: GR
authors.lastname: Blumenschein
authors.forename: Maciej J
authors.initials: MJ
authors.lastname: Krzakowski
authors.forename: Gilles
authors.initials: G
authors.lastname: Robinet
authors.forename: Benoit
authors.initials: B
authors.lastname: Godbert
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barlesi
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Govindan
authors.forename: Taral
authors.initials: T
authors.lastname: Patel
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Orlov
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wertheim
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Jiping
authors.initials: J
authors.lastname: Zha
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Premal H
authors.initials: PH
authors.lastname: Patel
authors.forename: See-Chun
authors.initials: SC
authors.lastname: Phan
authors.forename: Amy C
authors.initials: AC
authors.lastname: Peterson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D018592:Cross-Over Studies; D018572:Disease-Free Survival; D004311:Double-Blind Method; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D019859:Proto-Oncogene Proteins c-met; C584058:onartuzumab